Brain–body communication in metabolic control
Authors: Alessandro Furlan, Paul Petrus
Journal: Trends in Endocrinology and Metabolism (2023)

Energy homeostasis is achieved by the coordinated action of metabolic organs.The peripheral nervous system innervates organs, connects them with the brain, and plays an important role in controlling energy homeostasis.Brain–body communication is timed by molecular clocks controlling circadian rhythms.Brain–body coordination of metabolism is influenced by cognition and demographic aspects. A thorough understanding of the mechanisms controlling energy homeostasis is needed to prevent and treat metabolic morbidities. While the contribution of organs such as the liver, muscle, adipose tissue, and pancreas to the regulation of energy has received wide attention, less is known about the interplay with the nervous system. Here, we highlight the role of the nervous systems in regulating metabolism beyond the classic hypothalamic endocrine signaling models and discuss the contribution of circadian rhythms, higher brain regions, and sociodemographic variables in the energy equation. We infer that interdisciplinary approaches are key to conceptually advancing the current research frontier and devising innovative therapies to prevent and treat metabolic disease. A thorough understanding of the mechanisms controlling energy homeostasis is needed to prevent and treat metabolic morbidities. While the contribution of organs such as the liver, muscle, adipose tissue, and pancreas to the regulation of energy has received wide attention, less is known about the interplay with the nervous system. Here, we highlight the role of the nervous systems in regulating metabolism beyond the classic hypothalamic endocrine signaling models and discuss the contribution of circadian rhythms, higher brain regions, and sociodemographic variables in the energy equation. We infer that interdisciplinary approaches are key to conceptually advancing the current research frontier and devising innovative therapies to prevent and treat metabolic disease. 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In this review, we summarize the current understanding of the functional interplay between the major metabolic organs, the nervous system, and the circadian clock in the regulation of metabolic homeostasis. Further, we discuss the dynamics of this interplay in different environments and highlight the importance of considering the demographic context in which metabolic processes occur. We hope that this work will stimulate our readers to adopt multidisciplinary approaches when investigating the complex mechanisms regulating homeostasis and its disruption. Metabolic homeostasis is the result of the coordinated actions of several organs (Figure 1) that, under physiological conditions, modulate systemic macronutrient levels via energy storage [e.g., white adipose tissue (WAT) expansion], energy utilization (e.g., skeletal muscle contraction, adipose tissue thermogenesis) and by acting as control centers for energy utilization (e.g., pancreatic endocrine signaling, hepatic macronutrient conversion; Table 1). These mechanisms have been described in detail elsewhere [9.Priest C. Tontonoz P. Inter-organ cross-talk in metabolic syndrome.Nat. Metab. 2019; 1: 1177-1188Crossref PubMed Scopus (109) Google Scholar, 10.Ye J. Medzhitov R. Control strategies in systemic metabolism.Nat. Metab. 2019; 1: 947-957Crossref PubMed Scopus (22) Google Scholar, 11.Samuel V.T. Shulman G.I. The pathogenesis of insulin resistance: integrating signaling pathways and substrate flux.J. Clin. 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The theory that WAT storage capacity is associated with disease is supported by observations showing that the presence of a few relatively large fat cells (i.e., hypertrophic), rather than many smaller adipocytes, correlates with a higher incidence of type 2 diabetes [14.Acosta J.R. et al.Increased fat cell size: a major phenotype of subcutaneous white adipose tissue in non-obese individuals with type 2 diabetes.Diabetologia. 2016; 59: 560-570Crossref PubMed Scopus (144) Google Scholar,15.Weyer C. et al.Enlarged subcutaneous abdominal adipocyte size, but not obesity itself, predicts type II diabetes independent of insulin resistance.Diabetologia. 2000; 43: 1498-1506Crossref PubMed Scopus (599) Google Scholar]. When energy is needed, triglycerides are broken down through a process termed lipolysis. 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Exercise reduces blood glucose levels even under conditions of muscle insulin resistance, a hallmark of metabolic syndrome, by promoting glucose uptake independent of the insulin signaling pathway [11.Samuel V.T. Shulman G.I. The pathogenesis of insulin resistance: integrating signaling pathways and substrate flux.J. Clin. Invest. 2016; 126: 12-22Crossref PubMed Scopus (793) Google Scholar,18.Richter E.A. et al.Increased muscle glucose uptake after exercise: no need for insulin during exercise.Diabetes. 1985; 34: 1041-1048PubMed Scopus (0) Google Scholar] and improves metabolic health independent of weight loss [19.Pojednic R. et al.The benefits of physical activity for people with obesity, independent of weight loss: a systematic review.Int. J. Environ. Res. Public Health. 2022; 19: 4981Google Scholar]. Another channel of energy expenditure is via thermogenesis. When the external temperature is low, the brain activates the autonomic nervous system. Sympathetic fibers, innervating the adipose tissue, release noradrenaline and uncouple energy expenditure in the form of heat [20.Perez L.C. et al.Interventions associated with brown adipose tissue activation and the impact on energy expenditure and weight loss: a systematic review.Front Endocrinol. (Lausanne). 2022; 13: 3042Google Scholar]. The adipocytes capable of thermogenic activity are either brown [in brown adipose tissue (BAT)] or beige (in WAT). The discovery that humans have adipose tissue with thermogenic activity in adulthood [21.Cypess A.M. et al.Identification and importance of brown adipose tissue in adult humans.N. Engl. J. Med. 2009; 360: 1509-1517Crossref PubMed Scopus (3274) Google Scholar] opened a new avenue to reduce body weight and propelled the search for interventions activating BAT and/or converting white adipocytes to beige. In rodents, administering β3-adrenergic agonists increases energy expenditure and effectively reduces body weight [22.Himms-Hagen J. et al.Effect of CL-316,243, a thermogenic beta 3-agonist, on energy balance and brown and white adipose tissues in rats.Am. J. Phys. 1994; 266: R1371-R1382Crossref PubMed Google Scholar]. Prolonged cold exposure and sustained physical activity can reprogram adipocytes in the WAT from white to beige. This phenomenon, termed 'browning' and mediated by sympathetic-induced UCP1 expression in WAT, turns the reservoir tissue of the body into a metabolically active, heat-releasing organ. The clinical relevance of adipose tissue browning remains under debate [20.Perez L.C. et al.Interventions associated with brown adipose tissue activation and the impact on energy expenditure and weight loss: a systematic review.Front Endocrinol. (Lausanne). 2022; 13: 3042Google Scholar]. However, data from a recent study suggest that the decrease in energy expenditure over the past decades, which has contributed to the obesity pandemic, is due to lower basal metabolic rate (involving thermogenesis) rather than reduced locomotor activity [23.Speakman J.R. et al.Total daily energy expenditure has declined over the past three decades due to declining basal expenditure, not reduced activity expenditure.Nat. Metab. 2023; 5: 579-588Google Scholar]. Hence, increasing thermogenic capacity might be a complementary tool to sustain weight loss over longer periods. The pancreas and liver orchestrate macronutrient storage, release, and utilization. The pancreas senses systemic glucose levels and coordinates its uptake and release by the organs via the antagonistic function of the pancreatic hormones insulin and glucagon, respectively [24.Ojha A. et al.Current perspective on the role of insulin and glucagon in the pathogenesis and treatment of type 2 diabetes mellitus.Clin. 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Invest. 2012; 122: 4-12Crossref PubMed Scopus (513) Google Scholar]. Taken together, the coordinated action of WAT, muscle, BAT, pancreas, and liver is crucial for the storage, supply, and utilization of energy and to maintain metabolic homeostasis. It is well known that disruption of this regulatory system is implicated in the onset and progression of metabolic disease [9.Priest C. Tontonoz P. Inter-organ cross-talk in metabolic syndrome.Nat. Metab. 2019; 1: 1177-1188Crossref PubMed Scopus (109) Google Scholar,10.Ye J. Medzhitov R. Control strategies in systemic metabolism.Nat. Metab. 2019; 1: 947-957Crossref PubMed Scopus (22) Google Scholar]. Less appreciated is that peripheral neurons, by innervating virtually every organ and connecting them with the brain, represent an important component of such a control system. In the next section, we review both endocrine and neuronal routes enabling brain–body communication. The importance of hormones in the regulation of homeostasis is textbook knowledge. In the brain, molecularly encoded hypothalamic neurons receive information on the body's energy state via circulating hormones and cytokines secreted by the organs [26.Castillo-Armengol J. et al.Inter-organ communication: a gatekeeper for metabolic health.EMBO Rep. 2019; 20e47903Google Scholar] and coordinate the appropriate response to defend homeostasis [27.Buettner C. et al.Leptin controls adipose tissue lipogenesis via central, STAT3-independent mechanisms.Nat. Med. 2008; 14: 667-675Crossref PubMed Scopus (271) Google Scholar,28.Scherer T. et al.Brain insulin controls adipose tissue lipolysis and lipogenesis.Cell Metab. 2011; 13: 183Abstract Full Text Full Text PDF PubMed Scopus (195) Google Scholar]. While a critical role for extrahypothalamic areas in regulating energy homeostasis is emerging [29.Furlan A. et al.Neurotensin neurons in the extended amygdala control dietary choice and energy homeostasis.Nat. Neurosci. 2022; 25: 1470-1480Google Scholar,30.Schneeberger M. et al.Regulation of energy expenditure by brainstem GABA neurons.Cell. 2019; 178: 672-685.e12Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar], the function of peripheral neurons in regulating brain–body communication has just started to be investigated. The axons of somatosensory neurons [in the dorsal root ganglia (DRG)] and vagal sensory neurons [in the jugular and nodose ganglia (NG)] innervate the organs and detect changes in their microenvironment. This information is relayed to the brain, forming the ascending pathway. The thalamus and the brainstem are major recipients of somatosensory and vagal inputs. The functional relevance of vagal connections has been pioneered in studies on the gut–brain axis (discussed extensively elsewhere [31.Morais L.H. et al.The gut microbiota–brain axis in behaviour and brain disorders.Nat. Rev. Microbiol. 2021; 19: 241-255Crossref PubMed Scopus (589) Google Scholar]). Peripheral signals traveling along vagal afferents regulate various aspects of behavior and energy homeostasis [32.Berthoud H.-R. The vagus nerve, food intake and obesity.Regul. Pept. 2008; 149: 15-25Crossref PubMed Scopus (230) Google Scholar] and participate in the etiology of mental disorders [31.Morais L.H. et al.The gut microbiota–brain axis in behaviour and brain disorders.Nat. Rev. Microbiol. 2021; 19: 241-255Crossref PubMed Scopus (589) Google Scholar]. 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Endocrine and sensory feedback signals are integrated in the brain with salient external environmental stimuli (perceived via our senses; e.g., the smell and sight of food) to generate the appropriate behavioral (e.g., feeding), hormonal (e.g., via the hypothalamic-pituitary-adrenal axis), and autonomic-mediated physiological response to regulate homeostasis (Figure 2). Central activation of specialized sympathetic neurons [39.Furlan A. et al.Visceral motor neuron diversity delineates a cellular basis for nipple- and pilo-erection muscle control.Nat. Neurosci. 2016; 19: 1331-1340Crossref PubMed Scopus (61) Google Scholar], innervating the organs, coordinates metabolism by stimulating lipolysis (WAT) and gluconeogenesis (liver), inhibiting insulin production (pancreas), and inducing heat production (BAT) during a stressful event. When the stressor is removed, parasympathetic neurons are recruited to counteract sympathetic activity [40.Hyun U. Sohn J.-W. 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For instance, the unbiased molecular interrogation and functional characterization of parasympathetic neurons, and some of the largest sympathetic ganglia (e.g., the celiac ganglion) is lacking. Tracing studies from WAT revealed the existence of specialized cells in the brain receiving sensory inputs from adipose tissue and delivering autonomic outputs to the adipocytes, therefore enabling a loop for signals to be exchanged. Whether endocrine, somatosensorial, and vagal inputs work in parallel or in synergy to coordinate the effector response and whether organs other than WAT possess similar loop-circuitry paths to the brain is, to the best of our knowledge, unknown. Interestingly, some areas implicated in the regulation of circadian rhythms, including the central circadian pacemaker located in the suprachiasmatic nucleus, were traced from WAT, liver, and pancreas, indicating a link between the brain clocks and metabolic organ regulation. Furthermore, many neuronal connections with peripheral organs were traced in extrahypothalamic regions [43.Ryu V. Bartness T.J. Short and long sympathetic-sensory feedback loops in white fat.Am. J. Physiol. Regul. Integr. Comp. Physiol. 2014; 306: R886-R900Crossref PubMed Scopus (37) Google Scholar, 44.Rosario W. et al.The brain-to-pancreatic islet neuronal map reveals differential glucose regulation from distinct hypothalamic regions.Diabetes. 2016; 65: 2711-2723Crossref PubMed Scopus (65) Google Scholar, 45.Stanley S. et al.Identification of neuronal subpopulations that project from hypothalamus to both liver and adipose tissue polysynaptically.Proc. Natl. Acad. Sci. U. S. A. 2010; 107: 7024-7029Crossref PubMed Scopus (141) Google Scholar], suggesting a role for higher brain functions in metabolic control. In the next sections, we discuss the role of the circadian system and cognition in metabolic control, in the context of modern societies. 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At its core, a molecular clock comprises a transcriptional–translational feedback loop with the activators BMAL1 and CLOCK forming a heterodimer, binding to E-box elements, and transcribing thousands of genes [47.Koike N. et al.Transcriptional architecture and chromatin landscape of the core circadian clock in mammals.Science. 2012; 338: 349-354Crossref PubMed Scopus (998) Google Scholar]. Among these are the PER1-3 and CRY1-2 genes forming a negative feedback loop. Their corresponding proteins accumulate in the cytosol, where they are post-translationally modified and form heterodimers that translocate to the nucleus, where they negatively regulate the activity of BMAL1 and CLOCK. This loop takes about 1 day (i.e., 24 h) to complete and equips every nucleated cell with its timekeeping system controlling metabolic processes needed in a time-of-day-dependent manner. In addition, several metabolic pathways are integral components of the circadian machinery and provide substrates and/or co-substrates for epigenetic regulators [48.Berger S.L. Sassone-Corsi P. Metabolic signaling to chromatin.Cold Spring Harb. Perspect. Biol. 2016; 8a019463Crossref PubMed Scopus (101) Google Scholar]. CLOCK itself is an acetyltransferase protein regulating circadian rhythmicity by utilizing acetyl-CoA to mediate BMAL1 acetylation [49.Hirayama J. et al.CLOCK-mediated acetylation of BMAL1 controls circadian function.Nature. 2007; 450: 1086-1090Crossref PubMed Scopus (401) Google Scholar]. Moreover, the circadian transcriptional activators regulate NAD+ levels via transcriptional regulation of Nampt in the salvage pathway. 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Other metabolic pathways mediating circadian transcription via the molecular clock include the end-product in the pentose phosphate pathway O-GlcNac, which is the substrate for the post-translational modification O-GlcNacylation [51.Li M.D. et al.O-GlcNAc signaling entrains the circadian clock by inhibiting BMAL1/CLOCK ubiquitination.Cell Metab. 2013; 17: 303-310Abstract Full Text Full Text PDF PubMed Scopus (146) Google Scholar] as well as methionine metabolism-regulating methylation [52.Greco C.M. et al.S-Adenosyl-L-homocysteine hydrolase links methionine metabolism to the circadian clock and chromatin remodeling.Sci. Adv. 2020; 6eabc5629Google Scholar]. Hence, the molecular clock is bidirectionally coupled with metabolism by regulating metabolic processes that communicate back with the clock via epigenetic mechanisms. As described earlier, the metabolism is controlled by interorgan intercommunication allowing organ-specific circadian clocks to synchronize metabolically. 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However, the brain clock, including the central pacemaker in the suprachiasmatic nucleus, is sufficient to drive the rhythms of most circulatory metabolites and to restore glucose tolerance independent of any peripheral clocks [61.Petrus P. et al.The central clock suffices to drive the majority of circulatory metabolic rhythms.Sci. Adv. 2022; 8: 2896Google Scholar]. The systemic metabolic oscillations are likely to be driven by feeding–fasting rhythms; however, the restoration of glucose tolerance in mice with only the central clock is probably also regulated by neuronal communication with peripheral organs, as time-restricted feeding alone was shown to be insufficient to fully restore glucose tolerance [59.Smith J.G. et al.Liver